PROJECT SUMMARY The objective of this SBIR Phase I application is to select an optimized lead analog of ?-conotoxin RgIA to develop as a unique, non-opioid therapeutic for chronic neuropathic pain. RgIA, a peptide derived from the predatory marine cone snail Conus regius, is an inhibitor of the ?9?10 nicotinic acetylcholine receptor (nAChR), a novel genetically validated pain target. Our current lead candidate, KCP-400, potently and selectively inhibits both the rat and human target and displays analgesic efficacy in animal models of neuropathic pain. Moreover, RgIA and its analogs have anti-inflammatory and neuroprotective effects, thereby providing a neuropathic pain management strategy that includes both symptom reduction and disease modification. KCP-400 provides a novel, non-opioid mechanism of action that is distinct from all other commercially available products for the treatment of pain. Here, we propose to further optimize KCP-400 to increase its stability and bioavailability and enhance its therapeutic potential. The Specific Aims of this proposal are to: 1) optimize KCP-400 to increase its bioavailability while maintaining its target specificity; and 2) evaluate the efficacy and safety of the optimized KCP-400 in a nerve injury model of neuropathic pain. Peptide modifications to increase stability will include substitution of disulfide bridges with a stable backbone cross linker and peptide lipidation and pegylation. Analgesic potency of optimized KCP-400 will be evaluated through dose-response and comparative efficacy studies using the rat chronic constriction injury model of sciatic nerve injury and neuropathic pain. This work will provide an optimized preclinical development candidate for investigational new drug (IND)-enabling studies during SBIR Phase II. The significance of the program is its emphasis on an analgesic product with reduced susceptibility to analgesic tolerance and drug abuse and anticipated significant impact on reducing the global burden of neuropathic pain. Innovation relates to the focus on a stable ?-conotoxin RgIA analog with high potency and specificity for a new molecular target and disease- modifying neuroprotective activity. The key deliverable of this project is an optimized, long-acting, non-opioid analgesic drug candidate with good safety, tolerability, and efficacy in animal models of neuropathic pain.